Pretreatment with Transdermal Testosterone may Enhance Ovarian Response to FSH

The synergistic effects of androgens and follicle stimulating hormone (FSH) on folliculogenesis, a process critical for assisted reproduction techniques, have been previously established in primates. Now, a recent randomized clinical trial published in the journal Human Reproduction demonstrates that pretreatment with transdermal testosterone enhances the follicular response in poor IVF responders compared to the high-dose gonadotropin and minidose GnRH agonist protocol.
Francisco Jose Fabregues Gasol, from the Institut Clínic of Gynecology, Obstetrics and Neonatology, University of Barcelona, Spain, and colleagues, conducted a randomized trial to explore the efficacy of transdermal testosterone pretreatment in poor IVF responders. Sixty-two infertile women with a history of poor follicular response to IVF cycle were equally divided into two groups for their second IVF treatment. The first group received transdermal testosterone prior to standard ovarian stimulation, along with gonadotropin under pituitary suppression. On the other hand, the second group was administered with high-dose gonadotropin, along with a low-dose gonadotropin releasing hormone (GnRH) agonist protocol for ovarian stimulation.
Investigators observed that the first group had 32.2% cycles with low response, as compared to 71% in the other group. Also, ovum retrieval was more in the first group of patients (80.6%) in contrast to the second group (58.1%), with statistically significant difference (81.2% vs. 41.1%) in patients with normal basal FSH levels. The study results showed that the ovarian sensitivity to FSH and the response of follicles to gonadotropin treatment could be enhanced through transdermal testosterone pretreatment in poor IVF responders.
Earlier, Balasch and colleagues (Human Reproduction, 2006) conducted a self-controlled, therapeutic clinical trial on 25 infertile women with a history of poor follicular response, leading to cancellation of first and second IVF cycles. It was observed that pretreatment with transdermal testosterone could be an effective approach for poor IVF responders with normal basal FSH concentration but poor controlled ovarian stimulation response.
In a contradictory study, Massin, et al. (Human Reproduction, 2006) observed that testosterone administration does not significantly affect the ovarian response to FSH. The researchers conducted a double-blind study on women with a background of low response to controlled ovarian stimulation and a low hormonal ovarian reserve, to evaluate the effects of androgen application. The subjects were randomized to receive either transdermal testosterone or placebo gel for 15 days prior to gonadotropin administration for a second IVF cycle. Both cycles involved identical GnRH analogue and equal FSH daily doses. Plasma testosterone levels were substantially enhanced, with no similar effects on the antral follicular count in the test group. There was no significant difference in both the groups with regard to the main ovarian response parameters such as pre-ovulatory follicular number, and the count of total and mature oocytes and embryos. Based on their findings the investigators emphasized on further clinical trials to study the effects of optimal dose and duration for testosterone administration.
Conditions, such as high body mass index, pelvic adhesions, prior ovarian surgery, or progressive age, could be related with low ovarian response to gonadotropin treatment. The outcome of an IVF treatment is directly dependent on the number of embryos available. Poor ovarian response could lead to low embryo count, resulting in decreased pregnancy rates. Kailasam and colleagues (Human Reproduction, 2004) defined poor response in women aged <40 years, as cancellation of the cycle in patients on ≥300 IU FSH/day, (<3 pre-ovulatory follicle development), or the requirement for the total administration of ≥3000 IU FSH for sufficient follicular recruitment, substantiating oocyte retrieval.
Poor ovarian response to standard FSH treatment is a major concern in assisted reproduction processes. The current study, which demonstrates the enhanced ovarian sensitivity to gonadotropin in poor IVF responders, by pretreatment with transdermal testosterone, could serve as a novel approach to achieve enhanced success of IVF treatment.
References
1. Fábregues F, Peñarrubia J, Creus M, et al. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial. Hum Reprod. 2008 Dec 3. [Epub ahead of print]
2. Balasch J, Fábregues F, Peñarrubia J, et al. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum Reprod. 2006 Jul;21(7):1884-93.
3. Massin N, Cedrin-Durnerin I, Coussieu C, Galey-Fontaine J, Wolf JP, Hugues JN. Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study. Hum Reprod. 2006 May;21(5):1204-11.
4. Kailasam C, Keay SD, Wilson P, Ford WC, Jenkins JM. Defining poor ovarian response during IVF cycles, in women aged <40 years, and its relationship with treatment outcome. Hum Reprod. 2004 Jul;19(7):1544-7.